Endogenously occurring beta-carboline induces parkinsonism in nonprimate animals: a possible causative protoxin in idiopathic Parkinson's disease.
To examine whether simple beta-carbolines induce parkinsonian-like symptoms in vivo via N-methylation, the simple beta-carbolines norharman (NH), 2-mono-N-methylated norharmanium cation (2-MeNH+), and 9-mono-N'-methylnorharman (9-MeNH) were systematically administered to C57BL/6 mice for 7 days. These substances induced bradykinesia with reduction of locomotion activity. NH or 2-MeNH+ decreased dopamine (DA) contents to 50-70% of values in controls in the striatum and midbrain. 9-MeNH potently decreased not only DA but also serotonin content in various regions. Immunohistochemical examination revealed that the numbers of tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta of NH- and 9-MeNH-treated mice were diminished to 76 and 66% of values in control mice, respectively. The formation of a toxic metabolite, 2,9-di-N,N'-methylated norharmanium cation (2,9-Me2NH+), was 14 and eight times higher in the brain of mice receiving 9-MeNH than that in NH- and 2-MeNH+-treated mice, respectively. In cultured mesencephalic cells from rat embryo, 2,9-Me2NH+ selectively killed TH-positive neurons only at a lower dose but was toxic to all neurons at higher doses. Thus, the excess formation of 2,9-Me2NH+ would induce nonspecific neurotoxicity. These results indicated that 9-indole nitrogen methylation should be the limiting step in the development of the toxicity. NH, a selective dopaminergic toxin precursor, is sequentially methylated to form 2,9-Me2NH+, which could be an underlying factor in idiopathic Parkinson's disease.
Matsubara
K
K
Department of Hospital Pharmacy and Pharmacology, Asahikawa Medical College, Japan.
Gonda
T
T
Sawada
H
H
Uezono
T
T
Kobayashi
Y
Y
Kawamura
T
T
Ohtaki
K
K
Kimura
K
K
Akaike
A
A
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002243:Carbolines / Q000633:toxicity*; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D004622:Embryo, Mammalian; D006247:Harmine / Q000031:analogs & derivatives* / Q000633:toxicity; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity; D009638:Norepinephrine / Q000378:metabolism; D009928:Organ Specificity; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015306:Biogenic Monoamines; D002243:Carbolines; D009498:Neurotoxins; D015102:3,4-Dihydroxyphenylacetic Acid; C110418:9-mono-N'-methylnorharman; D012701:Serotonin; D006247:Harmine; D006897:Hydroxyindoleacetic Acid; C062099:2-methylnorharman; C010262:norharman; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D009638:Norepinephrine; D006719:Homovanillic Acid